Compositions comprising lipoxygenase inhibitors and cyclodextrin

ABSTRACT

The present invention is directed to formulations of inclusion complexes of lipoxygenase inhibitors and cyclodextrins having a therapeutically effective concentration of the lipoxygenase inhibitor, methods of making the same and methods of treating disease states using the same. Forming cyclodextrin complexes permits the enhancement of the aqueous solubility of lipoxygenase inhibitors which allows higher concentrations of the lipoxygenase in solution. Aqueous formulations of lipoxygenase inhibitors-cyclodextrin complexes are suitable for parenteral or oral administration for treating and/or preventing inflammatory disease states. The aqueous formulations can be lyophilized to prolong storage stability, assist in oral administration and/or provide for convenient and economical packaging.

This application claims the benefit of U.S. Provisional Application Ser.No. 60/736,980 filed on Nov. 15, 2005.

BACKGROUND OF THE INVENTION

The invention is directed to a composition comprising a lipoxygenaseinhibitor and a cyclodextrin, an inclusion complex of cyclodextrin and alipoxygenase inhibitor having a therapeutically effective concentrationof the lipoxygenase inhibitor, pharmaceutical compositions thereof,methods of making a formulation of an inclusion complex of cyclodextrinand a lipoxygenase inhibitor having a therapeutically effectiveconcentration of the lipoxygenase inhibitor, and therapeutic treatmentmethods using formulations of an inclusion complex of cyclodextrin and alipoxygenase inhibitor having a therapeutically effective concentrationof the lipoxygenase inhibitor. In particular, the invention is directedto formulations of an inclusion complex of a β-cyclodextrin orderivative thereof and a 5-lipoxygenase inhibitor having atherapeutically effective concentration of the lipoxygenase inhibitor,formulations of an inclusion complex of a β-cyclodextrin or derivativethereof and a 5-lipoxygenase inhibitor having a therapeuticallyeffective concentration of the lipoxygenase inhibitor, methods of makingformulations of an inclusion complex of a β-cyclodextrin or derivativethereof and a 5-lipoxygenase inhibitor having a therapeuticallyeffective concentration of the lipoxygenase inhibitor and therapeutictreatment methods using formulations of an inclusion complex of a13-cyclodextrin or derivative thereof and a 5-lipoxygenase inhibitorhaving a therapeutically effective concentration of the lipoxygenaseinhibitor. These formulations can be made as aqueous solutions foradministration via parenteral or oral routes, for example, or can be indried form. The dried formulation can be reconstituted foradministration or can be further processed for routes of administrationincluding, but not limited to, parenteral, oral, pulmonary, ophthalmic,nasal, rectal, vaginal, aural, topical, buccal, transdermal,intravenous, intramuscular, subcutaneous, intradermal, intraocular,intracerebral, intralymphatic, intraarticular, intrathecal andintraperitoneal.

Lipoxygenase enzymes play an important role in various diseases such asasthma, rheumatoid arthritis, gout, psoriases, allergic rhinitis,Crohn's disease, respiratory distress syndrome, chronic obstructivepulmonary disease, acne, atherosclerosis, aortic aneurysm, sickle celldisease, acute lung injury, ischemia/reperfusion injury, nasal polyposisand/or inflammatory bowel disease among others. Accordingly, compoundswhich inhibit lipoxygenase activity are useful in the treatment and/orprevention of such diseases. U.S. Pat. Nos. 4,873,259, 4,992,464, and5,250,565 which are incorporated herein by reference and made a partthereof, disclose certain lipoxygenase inhibitors, particularly 5-and/or 12-lipoxygenase inhibiting compounds, N-hydroxyurea 5- and/or12-lipoxygenase inhibiting compounds, methods of making 5- and/or12-lipoxygenase inhibiting compounds and pharmaceutical formulations of5 and 12-lipoxygenase inhibitors. One such N-hydroxyurea lipoxygenaseinhibitor is commonly known as zileuton. A solid dosage form of 600 mgzileuton for oral administration is used as a treatment for asthma.

Zileuton has the following chemical structure:

Zileuton may be used as a racemic mixture (about 50:50) of R(+) and S(−)enantiomers. Isomers of zileuton and their use in the inhibition oflipoxygenase activity have also been described. U.S. Pat. No. 5,629,337,which is incorporated herein by reference and made a part hereof,discloses the use of optically pure (-)-zileuton in the inhibition oflipoxygenase activity. WO 94/26268, which is incorporated herein byreference and made a part hereof, discloses the use of optically pure(+)-zileuton in the inhibition of lipoxygenase activity.

The low solubility in water of certain N-hydroxyurea 5- and/or12-lipoxygenase inhibitors prevents these beneficial agents from broaderuse than they would otherwise enjoy if aqueous formulations could beprepared at therapeutically effective concentrations. Zileuton, forexample, is soluble in methanol and ethanol, slightly soluble inacetonitrile, and practically insoluble in hexane and water (watersolubility 0.08-0.14 mg/ml at 25° C.). In addition to its poorsolubility, zileuton and likely other N-hydroxyurea lipoxygenaseinhibitors are predicted to be chemically unstable in aqueous solutionfor storage at room temperature for prolonged periods of time [InsertReference]. Degradation is consistent with specific hydronium- orwater-catalyzed hydrolysis to afford the carbamic acid, whichimmediately loses carbon dioxide to generate the hydroxylamine as shownbelow.

No buffer catalysis has been observed for zileuton. Using acid- andwater-catalyzed rate constants at 25° C., the pseudo first-order rateconstant is determined to be approximately 7.8×10⁻⁵ h⁻¹ over a pH rangeof about 3.5 to about 7.5. The shelf life at 10% drug loss is calculatedto be 57.3 days at an optimal pH of 5.6. The pH-rate profile at 25° C.,determined from rate data is as shown in FIG. 1.

Increasing the solubility of 5- and/or 12-lipoxygenase inhibitors suchas zileuton can lead to increased therapeutic efficacy and increasedtherapeutic applications of the drug. For example, aqueous solutionshaving therapeutically effective concentrations of lipoxygenaseinhibitors could be formulated into a ready-to-use injectable, such asan I.V. push or bolus injection. In addition, solution compositionscould be prepared having higher concentrations of the lipoxygenaseinhibitor for later dilution prior to injection. Injectable formulationsof lipoxygenase inhibitors could permit its use in treating a broadarray of disease states.

Once solution compositions having therapeutically effectiveconcentrations of lipoxygenase inhibitors have been prepared, solidconcentrates can be prepared by known methods. These soluble solidconcentrates could then be dissolved at the time of injection. Also,these solid concentrates could be compounded to produce a single dosageform such as tablets, capsules, lozenges, suppositories, etc.

Therefore, there is a need for soluble or solution compositions of 5-and/or 12-lipoxygenase inhibitors having a therapeutically effectiveconcentration of the lipoxygenase inhibitor for safe parenteral and/ororal administration, and in particular a soluble or solution compositionhaving therapeutically effective concentrations of a 5-lipoxygenaseinhibitor for parenteral administration. Moreover, a need exists forsoluble or solution compositions of 5- and/or 12-lipoxygenase inhibitorswhich can provide therapeutically effective concentrations forparenteral administration without causing adverse effects fromundesirably high concentrations of excipients.

SUMMARY OF THE INVENTION

The present invention is directed to compositions comprising aninclusion complex of a lipoxygenase inhibitor and a cyclodextrin.

In another embodiment of the present invention, a pharmaceuticalcomposition comprising an inclusion complex of a lipoxygenase inhibitorand cyclodextrin is provided, wherein the lipoxygenase inhibitor ispresent at a therapeutically effective concentration.

In another embodiment of the present invention, a pharmaceuticalcomposition comprising an inclusion complex of a lipoxygenase inhibitorand a cyclodextrin is provided, wherein the lipoxygenase inhibitor ispresent at a therapeutically effective concentration and thecyclodextrin is selected from the group consisting of β-cyclodextrin,γ-cyclodextrin, γ-cyclodextrin and derivatives thereof.

In a further embodiment of the present invention, a pharmaceuticalcomposition comprising an inclusion complex of a lipoxygenase inhibitorand a β-cyclodextrin or derivative thereof and a pharmaceuticallyacceptable excipient is provided, wherein the lipoxygenase inhibitor ispresent at a therapeutically effective concentration.

In another embodiment of the present invention, a pharmaceuticalcomposition comprising an inclusion complex of a lipoxygenase inhibitorand a cyclodextrin and pharmaceutically acceptable excipient isprovided, wherein the lipoxygenase inhibitor is present at atherapeutically effective concentration.

In yet another embodiment, a pharmaceutical composition comprising aninclusion complex of zileuton and a B-cyclodextrin and apharmaceutically acceptable excipient is provided, wherein zileuton ispresent at a therapeutically effective concentration.

In another embodiment of the present invention, a parenteral formulationcomprising an inclusion complex of a lipoxygenase inhibitor and acyclodextrin is provided wherein the lipoxygenase inhibitor is presentat a therapeutically effective concentration.

In yet another embodiment of the present invention, a dried formulationis provided comprising an inclusion complex of a lipoxygenase inhibitorand a cyclodextrin wherein the inclusion complex has a solubility of atleast 0.2 mg/mL and the lipoxygenase inhibitor is present at atherapeutically effective concentration.

In yet another embodiment of the present invention, a method of makingan aqueous solution of an inclusion complex of a 5-lipoxygenaseinhibitor and a β-cyclodextrin comprising the steps of: preparing anaqueous buffer solution; dissolving a β-cyclodextrin derivative in thebuffer solution; and adding a 5-lipoxygenase inhibitor to theβ-cyclodextrin derivative and buffer solution is provided.

In another aspect of the present invention, a method of treating amammal suffering from a condition mediated by lipoxygenase and/orleukotriene activity by administering the pharmaceutical compositioncomprising a lipoxygenase inhibitor and a cyclodextrin is provided,wherein said lipoxygenase inhibitor is present at a therapeuticallyeffective concentration of the lipoxygenase inhibitor.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the degradation reaction of zileuton in an aqueoussolution.

FIG. 2 shows the pH-rate profile of zileuton at 25° C.

DESCRIPTION OF THE INVENTION

As used herein, “a” or “an” are taken to mean one or more unlessotherwise specified.

It has been determined that the desired solubility enhancement of 5-and/or 12-lipoxygenase inhibitors can be achieved by forming aninclusion complex with a cyclodextrin. Cyclodextrins were fullydescribed by F. Schardinger and much of the older literature refers tocyclodextrins as Schardinger's dextrins. Cyclodextrins are cyclicoligosaccharides with hydroxyl groups on the outer surface and a cavityin the center. This cyclic orientation provides a truncated conestructure that is hydrophilic on the exterior and lipophilic on theinterior.

The most common cyclodextrins are α-, β-, and γ-cyclodextrins,consisting of 6, 7 and 8 α-1,4-linked glucose units, respectively. Thenumber of these units determines the size of the cavity.

Cyclodextrins are capable of forming inclusion complexes withhydrophobic molecules by taking up a whole molecule, or some part of it,into the cavity. The stability of the complex formed depends on how wellthe guest molecule fits into the cyclodextrin cavity. A compositioncomprising a lipoxygenase inhibitor and a cyclodextrin may includeinclusion complexes of the lipoxygenase inhibitor and the cyclodextrinas well as lipoxygenase inhibitor and cyclodextrin that are not part ofinclusion complexes.

α-, β-, and γ-cyclodextrins, have limited aqueous solubility and showsome toxicity when given by injection. For example, althoughβ-cyclodextrins form the most stable complex with many drugs, they havethe lowest water solubility of the cyclodextrins. Therefore, to overcomethese shortfalls, the cyclodextrin structure has been chemicallymodified to generate a safer cyclodextrin derivative with increasedsolubility. The modifications are typically made at one or more of the2, 3, or 6 position hydroxyl groups. Cyclodextrin derivatives have, forexample, been described in U.S. Pat. Nos. 5,134,127, 5,376,645,5,571,534, 5,874,418, 6,046,177 and 6,133,248, the contents of which areherein incorporated by reference and made a part hereof. As used herein,the term “cyclodextrin” is intended to encompass unmodifiedcyclodextrins as well as chemically modified derivatives thereof.

Although α-, β- and γ-cyclodextrins can be used for complex formationwith 5- and/or 12-lipoxygenase inhibitors, preferred cyclodextrins arethe β- and γ-cyclodextrins and even more preferred are theβ-cyclodextrins. Preferred β-cyclodextrins include2-hydroxypropyl-β-cyclodextrin and sulfobutyl derivatized β-cyclodextrin(described, for example, in U.S. Pat. Nos. 5,134,127, 5,376,645,5,874,418, 6,046,177 and 6,133,248). One such sulfobutyl derivatizedβ-cyclodextrin is sulfobutylether(7)-β-cyclodextrin.Sulfobutylether(7)-β-cyclodextrin is sold by CyDex, Inc. under thetradename CAPTISOL (“CAPTISOL Cyclodextrin”).

Preferred 5- and/ or 12-lipoxygenase inhibitors are of the type havingthe formula having the Formula (I):

wherein R₁ is selected from the group consisting of hydrogen, C1-C4alkyl, C2-C4 alkenyl, and NR₂R₃, wherein R₂ and R₃ are eachindependently selected from hydrogen, C1-C4 alkyl and hydroxyl, but R₂and R₃ are not simultaneously hydroxyl;

wherein X is oxygen, sulfur, SO₂, or NR₄, wherein R₄ is selected fromthe group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoyl. aroyl andalkylsufonyl;

A is selected from C1-C6 alkylene and C2-C6 alkenylene;

n is 1-5;

each Y is independently selected from hydrogen, halo, hydroxyl, cyano,halosubstituted alkyl, C1-C12 alkyl, C2-C12 alkenyl, C1-C12 alkoxy,C3-C8 cycloalkyl, C1-C8 thioalkyl, aryl, aryloxy, aroyl, C1-C12arylalkyl, C2-C12 arylalkenyl, C1-C12 arylalkoxy and C1-C12arylthioalkoxy, wherein substitutents are selected from halo, nitro,cyano, C1-C12 alkyl, alkoxy and halosubstituted alkyl;

Z is oxygen or sulfur; and

M is hydrogen, a pharmaceutically acceptable cation, aroyl or C1-C12alkoyl.

The substituent(s) Y and the linking group A may be attached at anyavailable position of either ring.

In an additional embodiment, the 5- and/or 12-lipoxygenase inhibitorsare of the type having the Formula (II):

where R₅ is C1 or C2 alkyl, or NR₆R₇ where R₆ and R₇ are independentlyselected from hydrogen and C1 or C2 alkyl; B is CH₂ or CHCH₃ ; and W isoxygen or sulfur.

The term “alkylene” is used herein to mean straight or branched chainspacer radicals, for example, —CH₂—, —C(CH₃)₂—, —CH(C₂H₅)—, —CH₂CH₂—,—CH₂CHCH₃—, —C(CH₃)₂—,C(CH₃)₂—, CH₂CH₂CH₂.

The term “alkenylene” is used herein to mean straight or branched chainunsaturated spacer radicals, for example, —CH═CH—, —CH═CHCH₂—,CH═CHCH(CH₃)—, —C(CH₃)═CHCH₂—, —CH₂CH═CHCH₂—, —C(CH₃)₂CH═CHC(CH₃)₂—.

The term “alkyl” is used herein to mean straight or branched chainradicals of 1 to 12 carbon atoms, including, but not limited to methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl.

The term “alkenyl” is used herein to mean straight or branched chainunsaturated radicals of 2 to 12 carbon atoms, including, but not limitedto ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl.

The term “cycloalkyl” is used herein to mean cyclic radicals, forexample, of 3 to 8 carbons, including, but not limited to cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl.

The term “alkoxy” is used herein to mean —OR₈ wherein R₈ is an alkylradical, including, but not limited to methoxy, ethoxy, isopropoxy,n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, and the like.

The term “thioalkyl” is used herein to mean —SR₉ wherein R₉ is an alkylradical, including, but not limited to thiomethyl, thioethyl,thioisopropyl, n-thiobutyl, sec-thiobutyl, isothiobutyl andtert-thiobutyl.

The term “alkoyl” is used herein to mean —COR₁₀ wherein R₁₀ is an alkylradical, including, but not limited to formyl, acetyl, propionyl,butyryl, isobutyryl and pivaloyl.

The term “carboalkoxy” is used herein to mean —COR₁₁, wherein R₁₁ is analkoxy radical, including, but not limited to carbomethoxy, carboethoxy,carboisopropoxy, carbobutoxy, carbosec-butoxy, carboiso-butoxy andcarbotert-butoxy.

The term “aryl” is used herein to mean substituted and unsubstitutedcarbocyclic and heterocylic aromatic radicals wherein the substituentsare chosen from halo, nitro, cyano, alkyl, alkoxy, and halosubstitutedalkyl, including, but not limited to phenyl, 1- or 2-naphthyl, 2-, 3-,or 4-pyridyl, 2- and 3-furyl.

The term “aroyl” is used herein to mean —COR₁₂ wherein R₁₂ is an arylradical, including, but not limited to benzoyl, 1-naphthoyl and2-naphthoyl.

The term “aryloxy” is used herein to mean —OR₁₃ wherein R₁₃ is an arylradical, including, but not limited to phenoxy, 1-naphthoxy and2-naphthoxy.

The term “arylalkoxy” is used herein to mean —OR₁₄ wherein R₁₄ is anarylalkyl radical, including, but not limited to phenylmethoxy (i.e.,benzyloxy), 4-fluorobenzyloxy, 1-phenylethoxy, 2-phenylethoxy,diphenylmethoxy, 1-naphthylmethoxy, 2-napthylmethoxy, 9-fluorenoxy, 2-,3- or 4-pyridylmethoxy and 2-, 3-, 4-, 5-, 6-, 7-, 8-quinolylmethoxy.

The term “arylthioalkoxy” is used herein to mean —SR₁₅ wherein R₁₅ is anarylalkyl radical, including, but not limited to phenylthiomethoxy(i.e., thiobenzyloxy), 4-fluorothiobenzyloxy, 1-phenylthioethoxy,2-phenylthioethoxy, diphenylthiomethoxy and 1-naphthylthiomethoxy.

The term “arylalkyl” is used herein to mean an aryl group appended to analkyl radical, including, but not limited to phenylmethyl (benzyl),1-phenylethyl, 2-phenylethyl, 1-naphthylethyl and 2-pyridylmethyl.

The term “arylalkenyl” is used herein to mean an aryl group appended toan alkenyl radical, including, but not limited to phenylethenyl,3-phenylprop-1-enyl, 3-phenylprop-2-enyl and 1-naphthylethenyl.

The term “alkylsulfonyl” is used herein to mean —SO₂ R₁₆ wherein R₁₆ isan alkyl radical, including, but not limited to methylsulfonyl (i.e.mesityl), ethyl sulfonyl and isopropylsulfonyl.

The terms “halo” and “halogen” are used herein to mean radicals derivedfrom the elements fluorine, chlorine, bromine, or iodine.

The term “halosubstituted alkyl” refers to an alkyl radical as describedabove substituted with one or more halogens, including, but not limitedto chloromethyl, trifluoromethyl, 2,2,2-trichloroethyl, and the like.

The term “pharmaceutically acceptable cation” refers to non-toxiccations including but not limited to cations based on the alkali andalkaline earth metals, such as sodium, lithium, potassium, calcium,magnesium, and the like, as well as nontoxic ammonium, quaternaryammonium, and amine cations, including, but not limited to ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine and ethylamine.

Inclusion complex formation of N-hydroxyurea 5- and/or 12-lipoxygenaseinhibitors is favored since this class of lipoxygenase inhibitors hasbeen shown to have therapeutic potential in clinical settings.Specifically, a preferred 5-lipoxygenase inhibitor, zileuton, has beenclinical approved for the treatment of asthma by oral administration.Zileuton has the following chemical formula:

Certain of the lipoxygenase inhibitors described herein, includingzileuton, contain one or more asymmetric centers and may thus give riseto enantiomers, diastereomers, and other stereoisomeric forms that maybe defined, in terms of absolute stereochemistry, as (R)- or (S)-. Thepresent invention is meant to include all such possible isomers,including racemic mixtures, optically pure forms and intermediatemixtures. Optically active (R)- and (S)-isomers may be prepared usingchiral synthons or chiral reagents, or resolved using conventionaltechniques. “Isomers” are different compounds that have the samemolecular formula. “Stereoisomers” are isomers that differ only in theway the atoms are arranged in space. “Enantiomers” are a pair ofstereoisomers that are non-superimposable mirror images of each other. A1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term“(±)” is used to designate a racemic mixture where appropriate.“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other. The absolutestereochemistry is specified according to the Cahn-Ingold-Prelog R-Ssystem. When a compound is a pure enantiomer the stereochemistry at eachchiral carbon may be specified by either R or S. Resolved compoundswhose absolute configuration is unknown can be designated (+) or (−)depending on the direction (dextro- or levorotatory) which they rotateplane polarized light at the wavelength of the sodium D line. When thecompounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended that the compounds include both E and Z geometric isomers.Likewise, all tautomeric forms are also intended to be included.

As used, herein, the term “zileuton” encompasses((±)-1-(1-benzo[b]thien-2-ylethyl)-1-hydroxyurea, the optically pureform of the (S)-enantiomer or (-)-isomer ofN-(1-benzo[b]thien-2-ylethyl)-N-hydroxyurea (described, for example, inU.S. Pat. No. 5,629,337), the optically pure form of (R)-enantiomer or(+)-isomer of N-(1-benzo[b]thien-2-ylethyl)-N-hydrxoyurea (described,for example, in WO 94/26268), mixtures of said (S)- and (R)-isomers inany ratio between 1:99 and 99:1, and polymorphic forms of zileuton thatare now known or later discovered.

In one embodiment, the lipoxygenase inhibitor compound is selected fromthe group consisting of((±)-1-(1-benzo[b]thien-2-ylethyl)-l-hydroxyurea, the optically pure(−)-isomer of N-(1-benzo[b]thien-2-ylethyl)-N-hydroxyurea and theoptically pure (+)-isomer ofN-(1-benzo[b]thien-2-ylethyl)-N-hydroxyurea.

In another embodiment of the present invention, a pharmaceuticalcomposition comprising an inclusion complex of a lipoxygenase inhibitorand a cyclodextrin is provided having a therapeutically effectiveconcentration of the lipoxygenase inhibitor. A therapeutically effectiveconcentration as used herein means a concentration that provides adosage of the drug that causes an ameliorative effect when administeredto a subject for treatment or prevention of an inflammatory diseasestate without having to administer more than the typical maximum volumefor the particular route of administration. With I.V. push formulations,for example, the concentration of the lipoxygenase inhibitor would haveto be high enough to provide a dosage that causes an ameliorative effectwithout having to administer more than the typical maximum volume for anI.V. push of about 100 mL. The dosage is in turn dependent on a numberof factors clinician take into consideration such as age, weight,diagnosis, disease stage, etc.

In one embodiment, a pharmaceutical composition comprising an inclusioncomplex of a lipoxygenase inhibitor and a cyclodextrin is provided,wherein the cyclodextrin is selected from the group consisting ofα-cyclodextrins, β-cyclodextrins, γ-cyclodextrins and derivativesthereof. The inclusion complex is preferably formed of a 5-lipoxygenaseinhibitor and a β-cyclodextrin or derivative thereof. In anotherembodiment, the pharmaceutical composition comprises a lipoxygenaseinhibitor of Formula (I) and a β-cyclodextrin or derivative thereof,wherein the lipoxygenase inhibitor is present in a therapeuticallyeffective amount. In another embodiment, the pharmaceutical compositioncomprises a lipoxygenase inhibitor of Formula (II) and a β-cyclodextrinor derivative thereof, wherein the lipoxygenase inhibitor is present ina therapeutically effective amount. Although many types ofβ-cyclodextrins can be used to form the complex, preferredβ-cyclodextrins are hydroxypropyl-β-cyclodextrins and sulfobutylderivatized β-cyclodextrins. A preferred lipoxygenase inhibitor andcyclodextrin inclusion complex is that of zileuton andsulfobutylether(7)-β-cyclodextrin.

The pharmaceutical compositions described herein can optionally includeone or more pharmaceutically acceptable excipients. Suchpharmaceutically acceptable excipients are well known in the art andinclude, for example, salts, surfactant(s), water-soluble polymers,preservatives, antimicrobials, antioxidants, cryo-protectants, wettingagents, viscosity agents, tonicity modifying agents, levigating agents,absorption enhancers, penetration enhancers, pH modifying agents,muco-adhesive agents, coloring agents, flavoring agents, dilutingagents, emulsifying agents, suspending agents, solvents, co-solvents,buffers, and combinations of these excipients.

Suitable surfactants can be selected from ionic surfactants, nonionicsurfactants, zwitterionic surfactants, polymeric surfactants,phospholipids, biologically derived surfactants, amino acids and theirderivatives or derivatives, combinations or conjugates of thesurfactants described above. Ionic surfactants can be anionic orcationic. The surfactants are present in the compositions in an amountof from about 0.01% to 10% w/v, and preferably from about 0.05% to about5% w/v.

Suitable anionic surfactants include but are not limited to: alkylsulfonates, aryl sulfonates, alkyl phosphates, alkyl phosphonates,potassium laurate, sodium lauryl sulfate, sodium dodecylsulfate, alkylpolyoxyethylene sulfates, sodium alginate, dioctyl sodiumsulfosuccinate, phosphatidic acid and their salts, sodiumcarboxymethylcellulose, bile acids and their salts, cholic acid,deoxycholic acid, glycocholic acid, taurocholic acid, andglycodeoxycholic acid, and calcium carboxymethylcellulose, stearic acidand its salts, calcium stearate, phosphates, sodium dodecylsulfate,carboxymethylcellulose calcium, carboxymethylcellulose sodium,dioctylsulfosuccinate, dialkylesters of sodium sulfosuccinic acid,sodium lauryl sulfate and phospholipids.

Suitable cationic surfactants include but are not limited to: quaternaryammonium compounds, benzalkonium chloride, cetyltrimethylammoniumbromide, chitosans, lauryldimethylbenzylammonium chloride, acyl camitinehydrochlorides, alkyl pyridinium halides, cetyl pyridinium chloride,cationic lipids, polymethylmethacrylate trimethylammonium bromide,sulfonium compounds, polyvinylpyrrolidone-2-dimethylaminoethylmethacrylate dimethyl sulfate, hexadecyltrimethyl ammonium bromide,phosphonium compounds, quaternary ammonium compounds,benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethylammonium chloride, coconut trimethyl ammonium bromide, coconut methyldihydroxyethyl ammonium chloride, coconut methyl dihydroxyethyl ammoniumbromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethylammonium chloride, decyl dimethyl hydroxyethyl ammonium chloridebromide, C12-15-dimethyl hydroxyethyl ammonium chloride, C12-15-dimethylhydroxyethyl ammonium chloride bromide, coconut dimethyl hydroxyethylammonium chloride, coconut dimethyl hydroxyethyl ammonium bromide,myristyl trimethyl ammonium methyl sulfate, lauryl dimethyl benzylammonium chloride, lauryl dimethyl benzyl ammonium bromide, lauryldimethyl (ethenoxy)4 ammonium chloride, lauryl dimethyl (ethenoxy)4ammonium bromide, N-alkyl (C12-18)dimethylbenzyl ammonium chloride,N-alkyl (C14-18)dimethyl-benzyl ammonium chloride,N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyldidecyl ammonium chloride, N-alkyl and (C12-14) dimethyl 1-napthylmethylammonium chloride, trimethylammonium halide alkyl-trimethylammoniumsalts, dialkyl-dimethylammonium salts, lauryl trimethyl ammoniumchloride, ethoxylated alkyamidoalkyldialkylammonium salts, ethoxylatedtrialkyl ammonium salts, dialkylbenzene dialkylammonium chloride,N-didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl ammoniumchloride monohydrate, N-alkyl(C12-14) dimethyl 1-naphthylmethyl ammoniumchloride, dodecyldimethylbenzyl ammonium chloride, dialkyl benzenealkylammonium chloride, lauryl trimethyl ammonium chloride, alkylbenzylmethyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C12trimethyl ammonium bromides, C15 trimethyl ammonium bromides, C17trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium chloride,poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammoniumchlorides, alkyldimethylammonium halogenides, tricetyl methyl ammoniumchloride, decyltrimethylammonium bromide, dodecyltriethylammoniumbromide, tetradecyltrimethylammonium bromide, methyl trioctylammoniumchloride, “POLYQUAT 10” (a mixture of polymeric quarternary ammoniumcompounds), , tetrabutylammonium bromide, benzyl trimethylammoniumbromide, choline esters, benzalkonium chloride, stearalkonium chloride,cetyl pyridinium bromide, cetyl pyridinium chloride, halide salts ofquaternized polyoxyethylalkylamines, “MIRAPOL” (polyquatemium-2)“Alkaquat” (alkyl dimethyl benzylammonium chloride, produced by Rhodia),alkyl pyridinium salts, amines, amine salts, imide azolinium salts,protonated quaternary acrylamides, methylated quaternary polymers, andcationic guar gum. benzalkonium chloride, dodecyl trimethyl ammoniumbromide, triethanolamine, and poloxamines.

Suitable nonionic surfactants include but are not limited to:polyoxyethylene fatty alcohol ethers, polyoxyethylene sorbitan fattyacid esters, alkyl polyoxyethylene sulfates, polyoxyethylene fatty acidesters, sorbitan esters, glyceryl esters, glycerol monostearate,polyethylene glycols, polypropylene glycols, polypropylene glycolesters, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, aryl alkylpolyether alcohols, polyoxyethylene-polyoxypropylene copolymers,poloxamers, poloxamines, methylcellulose, hydroxycellulose,hydroxymethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, noncrystalline cellulose, polysaccharides,starch, starch derivatives, hydroxyethylstarch, polyvinyl alcohol,polyvinylpyrrolidone, triethanolamine stearate, amine oxides, dextran,glycerol, gum acacia, cholesterol, tragacanth, glycerol monostearate,cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters,polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives,polyoxyethylene sorbitan fatty acid esters, polyethylene glycols,polyoxyethylene stearates, hydroxypropyl celluloses, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose,hydroxypropylmethylcellulose phthalate, noncrystalline cellulose,polyvinyl alcohol, polyvinylpyrrolidone,4-(1,1,3,3-tetramethylbutyl)phenol polymer with ethylene oxide andformaldehyde, poloxamers, alkyl aryl polyether sulfonates, mixtures ofsucrose stearate and sucrose distearate,p-isononylphenoxypoly(glycidol), decanoyl-N-methylglucamide,n-decyl-β-D-glucopyranoside, n-decyl -β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside,heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopy- ranoside,n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranosid- e;nonanoyl-N-methylglucamide, n-nonyl-β-D-glucopyranoside,octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside,octyl-β-D-thioglucopyranoside, PEG-cholesterol, PEG-cholesterolderivatives, PEG-vitamin A, PEG-vitamin E, and random copolymers ofvinyl acetate and vinyl pyrrolidone.

Zwitterionic surfactants are electrically neutral but possess localpositive and negative charges within the same molecule. Suitablezwitterionic surfactants include but are not limited to zwitterionicphospholipids. Suitable phospholipids include phosphatidylcholine,phosphatidylethanolamine, diacyl-glycero-phosphoethanolamine (such asdimyristoyl-glycero-phosphoethanolamine (DMPE),dipalmitoyl-glycero-phosphoethanolamine (DPPE),distearoyl-glycero-phosphoethanolamine (DSPE), anddioleolyl-glycero-phosphoethanolamine (DOPE)). Mixtures of phospholipidsthat include anionic and zwitterionic phospholipids may be employed inthis invention. Such mixtures include but are not limited tolysophospholipids, egg or soybean phospholipid or any combinationthereof.

Suitable polymeric surfactants include, but are not limited to,polyamides, polycarbonates, polyalkylenes, polyalkylene glycols,polyalkylene oxides, polyalkylene terepthalates, polyvinyl alcohols,polyvinyl ethers, polyvinyl esters, polyvinyl halides,polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes andcopolymers thereof, alkyl cellulose, hydroxyalkyl celluloses, celluloseethers, cellulose esters, nitro celluloses, polymers of acrylic andmethacrylic esters, methyl cellulose, ethyl cellulose, hydroxypropylcellulose, hydroxy-propyl methyl cellulose, hydroxybutyl methylcellulose, cellulose acetate, cellulose propionate, cellulose acetatebutyrate, cellulose acetate phthalate, carboxylethyl cellulose,cellulose triacetate, cellulose sulphate sodium salt, poly(methylmethacrylate), poly(ethylmethacrylate), poly(butylmethacrylate),poly(isobutylmethacrylate), poly(hexlmethacrylate),poly(isodecylmethacrylate), poly(lauryl methacrylate), poly(phenylmethacrylate), poly(methyl acrylate), poly(isopropyl acrylate),poly(isobutyl acrylate), poly(octadecyl acrylate), polyethylene,polypropylene poly(ethylene glycol), poly(ethylene oxide), poly(ethyleneterephthalate), poly(vinyl alcohols), poly(vinyl acetate), poly vinylchloride polystyrene and polyvinylpryrrolidone.

Suitable biologically derived surfactants include, but are not limitedto: lipoproteins, gelatin, casein, lysozyme, albumin, casein, heparin,hirudin, or other proteins.

Suitable buffers include, but are not limited to, sodium hydroxide,hydrochloric acid, tris buffer, mono-, di-, tricarboxylic acids andtheir salts, citrate buffer, phosphate buffer, glycerol-1-phosphate,glycercol-2-phosphate, acetate, lactate,tris(hydroxymethyl)aminomethane, aminosaccharides, mono-, di- andtrialkylated amines, meglumine (N-methylglucosamine), and amino acids.

The pharmaceutical compositions described herein may be administered byseveral routes of administration including, but not limited to,parenteral, oral, pulmonary, ophthalmic, nasal, rectal, vaginal, aural,topical, buccal, transdermal, intravenous, intramuscular, subcutaneous,intradermal, intraocular, intracerebral, intralymphatic, intraarticular,intrathecal and intraperitoneal routes of administration. The route ofadministration as well as the dosage of the composition to beadministered can be determined by the skilled artisan without undueexperimentation in conjunction with standard dose-response studies.Relevant circumstances to be considered in making those determinationsinclude the condition or conditions to be treated, the choice ofcomposition to be administered, the age, weight, and response of theindividual patient, and the severity of the patient's symptoms.

The excipient included within the pharmaceutical compositions of theinvention is chosen based on the expected route of administration of thecomposition in therapeutic applications. Accordingly, compositionsdesigned for oral, lingual, sublingual, buccal and intrabuccaladministration can be made without undue experimentation by means wellknown in the art, for example, with an inert diluent or with an ediblecarrier. The compositions may be enclosed in gelatin capsules orcompressed into tablets. For the purpose of oral therapeuticadministration, the pharmaceutical compositions of the present inventionmay be incorporated with excipients and used in the form of tablets,troches, capsules, elixirs, suspensions, syrups, wafers, chewing gumsand the like.

Solid dosage forms, such as tablets, pills and capsules, may alsocontain one or more binding agents, filling agents, suspending agents,disintegrating agents, lubricants, sweetening agents, flavoring agents,preservatives, buffers, wetting agents, disintegrants, effervescentagents, and other excipients. Such excipients are known in the art.Examples of filling agents are lactose monohydrate, lactose anhydrous,and various starches. Examples of binding agents are various cellulosesand cross-linked polyvinylpyrrolidone, microcrystalline cellulose,microcrystalline cellulose, and silicifized microcrystalline cellulose(SMCC). Suitable lubricants, including agents that act on theflowability of the powder to be compressed, are colloidal silicondioxide, talc, stearic acid, magnesium stearate, calcium stearate, andsilica gel. Examples of sweeteners are any natural or artificialsweetener, such as sucrose, xylitol, sodium saccharin, cyclamate,aspartame, and accsulfame K. Examples of flavoring agents are bubble gumflavor, fruit flavors, and the like. Examples of preservatives arepotassium sorbate, methylparaben, propylparaben, benzoic acid and itssalts, other esters of parahydroxybenzoic acid such as butylparaben,alcohols such as ethyl or benzyl alcohol, phenolic compounds such asphenol, or quarternary compounds such as benzalkonium chloride. Suitablediluents include pharmaceutically acceptable inert fillers, such asmicrocrystalline cellulose, lactose, dibasic calcium phosphate,saccharides, and/or mixtures of any of the foregoing. Examples ofdiluents include microcrystalline cellulose, lactose such as lactosemonohydrate, lactose anhydrous, dibasic calcium phosphate, mannitol,starch, sorbitol, sucrose and glucose. Suitable disintegrants includecorn starch, potato starch, maize starch, and modified starches,croscarmellose sodium, crosspovidone, sodium starch glycolate, andmixtures thereof. Examples of effervescent agents are effervescentcouples such as an organic acid and a carbonate or bicarbonate. Suitableorganic acids include, for example, citric, tartaric, malic, fumaric,adipic, succinic, and alginic acids and anhydrides and acid salts.Suitable carbonates and bicarbonates include, for example, sodiumcarbonate, sodium bicarbonate, potassium carbonate, potassiumbicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysinecarbonate, and arginine carbonate. Alternatively, only the acidcomponent of the effervescent couple may be present.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropyl parabens as preservatives, a dye and a flavoring such as cherryor orange flavor, and the like.

The present invention includes nasally administering to the mammal atherapeutically effective amount of the composition. As used herein,nasally administering or nasal administration includes administering thecomposition to the mucous membranes of the nasal passage or nasal cavityof the patient. As used herein, pharmaceutical compositions for nasaladministration of a composition prepared by well-known methods to beadministered, for example, as a nasal spray, nasal drop, suspension,gel, ointment, cream or powder. Administration of the composition mayalso take place using a nasal tampon or nasal sponge.

For topical administration, suitable formulations may includebiocompatible oil, wax, gel, powder, polymer, or other liquid or solidcarriers. Such formulations may be administered by applying directly toaffected tissues, for example, a liquid formulation to treat infectionof conjunctival tissue can be administered dropwise to the subject'seye, or a cream formulation can be administer to a wound site.

The compositions of the present invention can be administeredparenterally such as, for example, by intravenous, intramuscular,intrathecal or subcutaneous injection. Parenteral administration can beaccomplished by incorporating the compositions of the present inventioninto a solution or suspension. Such solutions or suspensions may alsoinclude sterile diluents such as water for injection, saline solution,fixed oils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents. Parenteral formulations may also includeantibacterial agents such as, for example, benzyl alcohol or methylparabens, antioxidants such as, for example, ascorbic acid or sodiumbisulfite and chelating agents such as EDTA. Buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose may also be added. The parenteralpreparation can be enclosed in ampules, disposable syringes or multipledose vials made of glass or plastic.

Rectal administration includes administering the pharmaceuticalcompositions into the rectum or large intestine. This can beaccomplished using suppositories or enemas. Suppository formulations caneasily be made by methods known in the art. For example, suppositoryformulations can be prepared by heating glycerin to about 120° C.,dissolving the pharmaceutical composition in the glycerin, mixing theheated glycerin after which purified water may be added, and pouring thehot mixture into a suppository mold.

Transdermal administration includes percutaneous absorption of thecomposition through the skin. Transdermal formulations include patches,ointments, creams, gels, salves and the like.

In addition to the usual meaning of administering the formulationsdescribed herein to any part, tissue or organ whose primary function isgas exchange with the external environment, for purposes of the presentinvention, “pulmonary” is also meant to include a tissue or cavity thatis contingent to the respiratory tract, in particular, the sinuses. Forpulmonary administration, an aerosol formulation containing the activeagent, a manual pump spray, nebulizer or pressurized metered-doseinhaler as well as dry powder formulations are contemplated. Suitableformulations of this type can also include other agents, such asantistatic agents, to maintain the disclosed compounds as effectiveaerosols.

A drug delivery device for delivering aerosols comprises a suitableaerosol canister with a metering valve containing a pharmaceuticalaerosol formulation as described and an actuator housing adapted to holdthe canister and allow for drug delivery. The canister in the drugdelivery device has a head space representing greater than about 15% ofthe total volume of the canister. Often, the polymer intended forpulmonary administration is dissolved, suspended or emulsified in amixture of a solvent, surfactant and propellant. The mixture ismaintained under pressure in a canister that has been sealed with ametering valve.

In one embodiment, the molar ratio of the lipoxygenase inhibitor to thecyclodextrin is preferably from about 10:1 to about 1:10. In anotherembodiment, the molar ratio of the lipoxygenase inhibitor is from about5:1 to about 1:5. In yet another embodiment, the ratio is from about 1:1to about 1:5. The concentration of the lipoxygenase inhibitor ispreferably from about 0.1 mg/mL to about 200 mg/mL, more preferably fromabout 1 to about 100 mg/ml, more preferably from about 5 mg/mL to about50 mg/mL and even more preferably from about 8 mg/mL to about 30 mg/mLand the concentration of the cyclodextrin is preferably from about 4 mMto about 900 mM, more preferably from about 20 mM to about 500 mM andeven more preferably from about 30 mM to about 200 mM. In oneembodiment, the lipoxygenase compositions of the present invention donot include a buffer. In another embodiment, the compositions optionallymay include a buffer. Suitable buffer solutions include, but are notlimited to, solutions of sodium hydroxide, hydrochloric acid, trisbuffer, mono-, di-, tricarboxylic acids and their salts, citrate buffer,phosphate buffer, glycerol-1-phosphate, glycercol-2-phosphate, acetate,lactate, tris(hydroxymethyl)aminomethane, aminosaccharides, mono-, di-and trialkylated amines, meglumine (N-methylglucosamine), succinate,benzoate, tartrate, carbonate and amino acids. In a preferredembodiment, the buffer is a citrate buffer, and even more preferably acitrate buffer present at a concentration of from about 2 mM to about500 mM. The compositions preferably have a pH of from about 3 to about9. The compositions are preferably suited to be administeredparenterally, and more preferably, administered as an I.V. push or bolusinjection.

In another embodiment of the present invention, a method of making apharmaceutical composition comprising an inclusion complex of alipoxygenase inhibitor and a cyclodextrin is provided by preparing anaqueous buffer solution, dissolving a cyclodextrin in the buffersolution, and adding a lipoxygenase inhibitor to the cyclodextrin andbuffer solution.

The method preferably further comprises stirring and/or sonicating thelipoxygenase inhibitor and cyclodextrin solution. The method alsopreferably comprises adjusting the pH of the buffer solution to be fromabout 3 to about 9. In one embodiment, the solution has a concentrationof from about 0.1 mg/mL to about 200 mg/mL of the lipoxygenaseinhibitor. In another embodiment, the concentration of lipoxygenaseinhibitor is from about 5 mg/mL to about 50 mg/mL, and in yet anotherembodiment, the concentration is from about 8 mg/mL to about 30 mg/mL.In a further embodiment, the cyclodextrin is present at a concentrationof from about 4 mM to about 900 mM, in another embodiment, from about 20mM to about 500 mM and in yet another embodiment, from about 30 mM toabout 500 mM. A preferred buffer is a citrate buffer present at aconcentration of from about 2 mM to about 500 mM. In an additionalembodiment, a composition comprising a lipoxygenase inhibitor and acyclodextrin may comprise higher concentrations of a lipoxygenaseinhibitor and a cyclodextrin than those described above. Suchcompositions can be diluted prior to administration to a patient.

A preferred lipoxygenase inhibitor is an N-hydroxyurea lipoxygenaseinhibitor (described, for example, U.S. Pat. Nos. 4,873,259, 4,992,464,5,250,565 and 5,629,337, and WO 94/26268). In a further embodiment, thelipoxygenase inhibitor is zileuton and the cyclodextrin is aβ-cyclodextrin or derivative thereof. In a further preferred embodiment,the cyclodextrin is sulfobutylether(7)-β-cyclodextrin.

While it is possible to solubilize the lipoxygenase inhibitor in anexcess of cyclodextrin when forming the inclusion complex, it can bedesirable to minimize the amount of cyclodextrin needed to solubilizethe drug, especially if the solution is to be administered parenterally.

In one embodiment, the stoichiometry of complexation of adrug-cyclodextrin complex is 1:1. In other words, the inclusion complexcan include at least one molecule/mole of cyclodextrin for everymolecule/mole of drug. In order to determine the minimum amount ofcyclodextrin needed to solubilize the drug, a plot of drug solubilityversus cyclodextrin concentration preferably should be carried out. Frominterpolation of the plot, a formulation can be prepared that minimallycontains the amount of cyclodextrin needed to dissolve the lipoxygenaseinhibitor. Since the stoichiometry of complexation will likely varydepending on the particular complex of 5- and/or 12-lipoxygenaseinhibitor and cyclodextrin, it is desirable that such a solubility plotbe conducted for each specific lipoxygenase-cyclodextrin complex. Asolubility plot carried out on the zileuton-CAPTISOL Cyclodextrincomplex is described below in Example 1.

Interpolation of the plot described in Example 1, the stoichiometry ofcomplexation for the zileuton-CAPTISOL Cyclodextrin embodiment wasdetermined to be about 1:1.8. In other words, the minimal amount ofCAPTISOL Cyclodextrin needed to dissolve about one mole of zileuton in apreferred concentration range of about 5 to about 30 mg/mL is about 1.8moles of CAPTISOL Cyclodextrin. As noted above, an excess ofcyclodextrin can be used to dissolve the lipoxygenase inhibitor,particularly if the cyclodextrin does not produce any adverse effectsupon administration of the formulation.

While a solution pH of 5.5 was initially selected for thezileuton-CAPTISOL Cyclodextrin complex, this may not be the case withother lipoxygenase-cyclodextrin complexes. As described in Example 2,further testing was done to determine an optimal pH range to maximizestability of the zileuton-CAPTISOL Cyclodextrin complex. Such testingmay also be required to determine the optimal pH for otherlipoxygenase-cyclodextrin complexes.

In addition to preparing solution formulations of lipoxygenaseinhibitor-cyclodextrin complexes, solid formulations can be prepared byknown methods, such as lyophilization, spray-drying and/orsuper-critical fluid extraction. These solid concentrates can then bere-suspended at the time of injection. Also, these solid concentratesmay also be compounded to produce a single dosage form such as tablets,capsules, lozenges, suppositories, coated tablets, capsules, ampoules,suppositories, delayed release formulations, controlled releaseformulations, extended release formulations, pulsatile releaseformulations, immediate release formulations, gastroretentiveformulations, effervescent tablets, fast melt tablets, oral liquid andsprinkle formulations. The solid concentrates may also be formulated ina form selected from the group consisting of a patch, a powderpreparation for inhalation, a suspension, an ointment and an emulsion.

These dried formulations may be preferred for lipoxygenaseinhibitor-cyclodextrin complexes that have poor long-term stability insolution form.

The dried formulation can be provided as is to the healthcare providerwhere it can be resolubilized in an appropriate diluent, such as adiluent suitable for parenteral or oral administration. The sameformulation can be prepared by known methods for administration to asubject by various routes, such as, but are not limited to, parenteral,oral, pulmonary, ophthalmic, nasal, rectal, vaginal, aural, topical,buccal, transdermal, intravenous, intramuscular, subcutaneous,intradermal, intraocular, intracerebral, intralymphatic, intraarticular,intrathecal and intraperitoneal.

In addition, the dried formulation can be resolubilized to produce aready-to-use injectable formulation, preferably as an I.V. push or bolusinjection. The lyophilized formulation can be resolubilized to a highconcentration dosage which can be further diluted for injection. In apreferred embodiment, the lyophilized formulations are resolubilized forparenteral administration to provide a concentration range of thelipoxygenase inhibitor from about 0.1 to about 200 mg/mL, morepreferably from about 5 to about 50 mg/mL, and even more preferably fromabout 8 to about 30 mg/mL

For the purpose of preparing a stabilized dry solid, bulking agents suchas mannitol, sorbitol, sucrose, starch, lactose, trehalose or raffinosemay be added prior to lyophilization. The solution may be lyophilizedusing any applicable program for lyophilization, for example:

-   -   loading at ±25° C.;    -   cooling down to −45° C. in 1 hour;    -   holding time at −45° C. for 3.5 hours;    -   mean drying for 33 hours with continual increase of temperature        to +15° C. at a pressure of 0.4 mbar; and    -   final drying for 10 hours at +20° C. at a pressure of 0.03 mbar        cryo protectant: mannitol.

Preferably, in order to aid in the selection of an appropriatelyophilization cycle for the particular lipoxygenaseinhibitor-cyclodextrin complex solution freeze-thaw stability and DSCanalysis of the solution formulation should be conducted.

Sterilization can be accomplished by a variety of methods known in theart including but not limited to heat sterilization, filtration, andirradiation. Sterilization can be accomplished by sterile filtration ofthe final lipoxygenase-cyclodextrin solution formulation. Any remainingsteps, such as lyophilization or packaging, must then be carried outunder sterile operating conditions. Typical sterile filtration methodsinclude, for example, pre-filtration first through a 3.0 micrometerfilter followed by filtration through a 0.45 micrometer particle filter,followed by filtration through two redundant 0.2 micrometer membranefilters.

The lipoxygenase inhibitor-cyclodextrin formulation whether as asolution formulation or a lyophilized formulation can be sterilized byheat sterilization, irradiation or other known sterilization methods,such as high pressure sterilization.

The pharmaceutical compositions described herein may be co-administeredwith one or more additional agents separately or in the sameformulation. Such additional agents include, for example,anti-histamines, beta agonists (e.g., albuterol), antibiotics,anti-inflammatories (e.g. ibuprofen, prednisone (corticosteroid) orpentoxifylline), anti-fungals, (e.g. Amphotericin B, Fluconazole,Ketoconazol, and Itraconazol), steroids, decongestants,bronchodialators, and the like. The formulation may also containpreserving agents, solubilizing agents, chemical buffers, surfactants,emulsifiers, colorants, odorants and sweeteners.

The pharmaceutical composition described herein can be used to treat apatient suffering from a condition mediated by lipoxygenase and/orleukotriene activity. In one embodiment, the condition is mediated by 5-and/or 12-lipoxygenase activity. In another embodiment, the condition isan inflammatory condition.

Conditions mediated by lipoxygenase and/or leukotriene activity include,but are not limited to asthma, rheumatoid arthritis, gout, psoriases,allergic rhinitis, respiratory distress syndrome, chronic obstructivepulmonary disease, acne, atopic dermatitis, atherosclerosis, aorticaneurysm, sickle cell disease, acute lung injury, ischemia/reperfusioninjury, nasal polyposis, inflammatory bowel disease (including, forexample, ulcerative colitis and Crohn's disease), irritable bowelsyndrome, cancer, tumors, respiratory syncytial virus, sepsis, endotoxinshock and myocardial infarction.

In one embodiment, the condition mediated by lipoxygenase and/orleuktoriene activity is an inflammatory condition. Inflammatoryconditions include, but are not limited to, appendicitis, peptic,gastric or duodenal ulcers, peritonitis, pancreatitis, acute or ischemiccolitis, diverticulitis, epiglottitis, achalasia, cholangitis,cholecystitis, hepatitis, inflammatory bowel disease (including, forexample, Crohn's disease and ulcerative colitis), enteritis, Whipple'sdisease, asthma, chronic obstructive pulmonary disease, acute lunginjury, ileus (including, for example, post-operative ileus), allergy,anaphylactic shock, immune complex disease, organ ischemia, reperfusioninjury, organ necrosis, hay fever, sepsis, septicemia, endotoxic shock,cachexia, hyperpyrexia, eosinophilic granuloma, granulomatosis,sarcoidosis, septic abortion, epididymitis, vaginitis, prostatitis,urethritis, bronchitis, emphysema, rhinitis, cystic fibrosis,pneumonitis, pneumoultramicroscopic silicovolcanoconiosis, alvealitis,bronchiolitis, pharyngitis, pleurisy, sinusitis, influenza, respiratorysyncytial virus, herpes, disseminated bacteremia, Dengue fever,candidiasis, malaria, filariasis, amebiasis, hydatid cysts, burns,dermatitis, dermatomyositis, sunburn, urticaria, warts, wheals,vasulitis, angiitis, endocarditis, arteritis, atherosclerosis,thrombophlebitis, pericarditis, myocarditis, myocardial ischemia,periarteritis nodosa, rheumatic fever, Alzheimer's disease, coeliacdisease, congestive heart failure, adult respiratory distress syndrome,meningitis, encephalitis, multiple sclerosis, cerebral infarction,cerebral embolism, Guillame-Barre syndrome, neuritis, neuralgia, spinalcord injury, paralysis, uveitis, arthritides, arthralgias,osteomyelitis, fasciitis, Paget's disease, gout, periodontal disease,rheumatoid arthritis, synovitis, myasthenia gravis, thryoiditis,systemic lupus erythematosus, Goodpasture's syndrome, Behcet's syndrome,allograft rejection, graft-versus-host disease, Type I diabetes,ankylosing spondylitis, Berger's disease, Type II diabetes, Retier'ssyndrome, or Hodgkins disease.

In a further embodiment, the inflammatory condition is selected from thegroup consisting of rheumatoid arthritis, asthma, chronic obstructivepulmonary disease, acute lung injury, inflammatory bowel disease,allergy, organ ischemia, reperfusion injury, rhinitis, dermatitis,atherosclerosis, myocardial ischemia and adult respiratory distresssyndrome.

EXAMPLE 1 Solubility Study

The solubility of zileuton at 5 and 25° C. in the presence of CAPTISOLCyclodextrin was measured. A series of CAPTISOL Cyclodextrin solutions(100 to 400 mg/mL, or about 45 to 182 mM) were equilibrated with a molarexcess of zileuton (100 mg/mL, or 423 mM). (See Table below.) Solutionswere buffered, preferrably with 10 mM citrate buffer, to a pH of 5.5.Drug Concentration CAPTISOL Cyclodextrin (mg/mL) concentration (mg/mL)100 None 100 25 100 50 100 100 100 250 100 300 100 350 100 400

These mixtures were sonicated and then stirred for 1 week at 5° C.Another similar set of samples, prepared as described above, wereagitated in a controlled temperature chamber at 25° C.

After one week of equilibration, each sample was centrifuged, and thesupernatant analyzed for drug concentration by simple UV assay. Byplotting molar solubility of zileuton in each sample versus CAPTISOLCyclodextrin concentration, the stoichiometry of complexation (1 :1 or1:2, for example), and the binding constant, K was determined. For a 1:1complex, the equation is [Higuchi T, Connors K A. Phase-solubilitytechniques. Adva Anal Chem Instr. 1965;4:212-217]:$S = {S_{0} + {\frac{K\quad S_{0}}{1 + {K\quad S_{0}}}C_{T}}}$S is the total drug solubility, bound to cyclodextrin and unbound, C_(T)is the total concentration of cyclodextrin in the sample, S₀ is theintrinsic solubility of the drug (solubility with cyclodextrin absent),and K is the 1:1 binding constant. From the slope, and knowledge of S₀,K can be determined. Results of this analysis are plotted in FIG. 2, andindicate a 1:1 binding constant of about 3,200 at 25° C. The molar ratioof cyclodextrin to drug at the solubility limit (25° C.) isapproximately 1.7:1.

EXAMPLE 2 Stability and Stress Testing

A feasibility study to investigate the stability ofzileuton-cyclodextrin solutions formulated at three different initial pHvalues (approximately 4.0, 5.5, and 7.0) was conducted. The solutionswere formulated to contain 15 mg/mL zileuton, 250 mg/mL CAPTISOLCyclodextrin, and 10 mM citrate buffer. Stress testing was performed bysubjecting samples at each pH to both one and three freeze-thaw cycles.In addition, samples at each pH were stored at 5° C., 25° C., and 40° C.for a total of 8 weeks. At each testing interval, the samples werevisually inspected and analyzed for pH, osmolality, color, and drugpotency.

Zileuton-CAPTISOL Cyclodextrin formulations containing 15 mg/mL of drugand 250 mg/mL CAPTISOL Cyclodextrin were prepared at pH 4, 5.5, and 7,with an appropriate buffer, preferably 10 mM citrate, and stored at 5,25 and 40° C for 8 weeks. Based on literature data [Alvarez, F J; Slade,R T. Kinetics and mechanism of degradation of zileuton, a potent5-lipoxygenase inhibitor. Pharm. Res., 1992, 9(11): 1465-1473], zileutonin solution is expected to have adequate short-term stability (at least1 month at 25° C.) over a pH range of 4 to 7.

A buffer stock solution (A) of 10 mM citric acid was prepared by addingdistilled water to 1.9212 g citric acid anhydrous to a final volume of1L. A buffer stock solution (B) of 10 mM sodium citrate was prepared byadding distilled water to 2.9411 g sodium citrate dihydrate(Na₃C₆H₅O₇.2H₂O) to a final volume of 1L.

The above stock buffer solutions A and B were combined to prepare buffersolutions for each formulation as shown in the Table 3 below: TABLE 3Preparation of Buffer Solutions Citric Acid Sodium Citrate Buffer (mL)(mL) Measured pH 10 mM citrate pH q.s. to 200 mL 72 3.94 4.0 ± 0.2 10 mMcitrate pH 58 q.s. to 200 mL 5.47 5.5 ± 0.2 10 mM citrate pH  6 q.s. to200 mL 6.97 7.0 ± 0.2

The above buffer solutions were then used to make the three solutions atapproximate pH 4.0, 5.5, and 7.0. All three solutions contained 15 mg/mLzileuton and 250 mg/mL CAPTISOL Cyclodextrin. Solution pH measurementswere performed after addition and dissolution of zileuton and CAPTISOLCyclodextrin (and sodium hydroxide for pH 5.5 and 7.0), but before finalthe final dilution step. Solutions were pipetted into amber glass vialsand sealed with rubber stoppers and aluminum crimp caps. Vials werefilled as 2-mL fill for potency testing and as 10-mL fill formeasurement of pH, osmolality, color, and visual inspection. Inaddition, amber glass vials were filled (10 mL) for stress testing(freeze-thaw). All vials were stored in controlled temperature chambersat 5° C., 25° C., and 40° C.

Samples were pulled for testing at the time-zero, 1 week, 2 week, 4week, and 8 week intervals.

Stress Testing (Freeze-Thaw)

Vials used for 1- and 3-cycle stress testing were stored at −20° C. forapproximately 24 hours and then were placed in a 25° C. storage chamberfor approximately 1 hr 20 minutes, at which point the samples werethawed. The 1-cycle stress samples were then tested for pH, osmolality,color, visual inspection and potency. The 3-cycle stress samples wereplaced back into the −20° C. chamber for approximately 24 hours and werethen allowed to thaw at 25° C. for approximately 1 hour. The sampleswere placed back into the −20° C. chamber for approximately 26.5 hoursand were then allowed to thaw at 5° C. for approximately 3 days untiltesting was performed for pH, osmolality, color, visual inspection andpotency.

Results of the potency, pH, visual inspection, osmolality, and colortesting for the 1-cycle and 3-cycle freeze-thaw stress testing are givenin Tables 4-6. TABLE 4 Freeze-Thaw Stress Data for pH 4.0 Solution TestPotency Measured Color Osmolality Interval (mg/mL) pH Visual (KSU)(mOsmol/kg) Time Zero 15.14 4.06 Pass 0 864 1 Cycle 14.58 4.07 Pass 20862 3 Cycle 15.21 4.05 Pass 16 868

TABLE 5 Freeze-Thaw Stress Data for pH 5.5 Solution Test PotencyMeasured Color Osmolality Interval (mg/mL) pH Visual (KSU) (mOsmol/kg)Time Zero 14.64 5.61 Pass 19 852 1 Cycle 14.46 5.54 Pass 19 857 3 Cycle14.60 5.47 Pass 19 864

TABLE 6 Freeze-Thaw Stress Data for pH 7.0 Solution Test PotencyMeasured Color Osmolality Interval (mg/mL) pH Visual (KSU) (mOsmol/kg)Time Zero 14.51 6.93 Pass 15 863 1 Cycle 14.41 6.94 Pass 15 860 3 Cycle14.55 6.97 Pass 17 866

The potency, pH, color, and osmolality data for the 1-cycle and 3-cyclefreeze-thaw samples showed no significant changes. Furthermore, nosignificant particulates were observed upon visual inspection in any ofthe samples. Therefore, all samples appear to be stable against stressesimparted by freezing and thawing.

Stability of Samples Stored Through 8 weeks in Controlled TemperatureChambers

All 5° C. and 25° C. samples exhibited insignificant changes in potencyover the 8 week storage period, and only modest pH changes, verifyingthe stability of these formulations at 5° C. and 25° C. across theentire storage period. Osmolality data indicated that the osmolality ofthese formulations ranged from 843-903 mOsmol/kg.

EXAMPLE 3

The purpose of this study is to evaluate the stability of azileuton-cyclodextrin solution, adjusted to an initial target pH of 4,and at lower drug and cyclodextrin levels (10 mg/mL zileuton, 167 mg/mLCAPTISOL Cyclodextrin), and buffered with 10 mM citrate.

A cyclodextrin solution was prepared by dissolving 417 g of CAPTISOLCyclodextrin in approximately 1.75 L of 10 mM citrate buffer. 25 g ofzileuton was weighed and transferred to the cyclodextrin solution withstirring. After complete dissolution, the formulation was tested for pHand confirmed to be at pH 4. The solution was then diluted with citratebuffer to bring the final volume of the solution to 2.5 L. An aliquot ofthis solution was tested for pH and was confirmed to be 4.

By a similar mixing procedure, a control solution was prepared withoutdrug.

Glass vials were filled with the experimental and control formulations,and stored at 5° C., 25° C., and 40° C. Samples were pulled for testingat the time-zero, two-week, one-month, and three-month intervals.Testing was performed for potency, pH, visual inspection, osmolality(time-zero only), and color. Instrumental particle analysis was alsoperformed at each interval.

The data indicated that the samples stored at 5 and 25° C. showed nosignificant change in drug level through 3 months. Visual inspection ofthe samples indicated no visible precipitation, or other phaseseparation. Instrumental particle counts demonstrated that the countsper mL for all solution units tested were within the current USPinstrumental particle limits for 30 mL Small Volume Injection (SVI)solutions. The osmolality of the formulation at time-zero was 529mOsmol/kg.

EXAMPLE 4 Stability of a zileuton-CAPTISOL Cyclodextrin Formulation Uponlyophilization, Followed by Reconstitution

The purpose of this study was to determine stability of azileuton-cyclodextrin formulation (15 mg/mL zileuton, 250 mg/mL CAPTISOLCyclodextrin, pH 4) that had been subjected to lyophilization.Lyophilized vials of zileuton-cyclodextrin formulation werereconstituted and analyzed to determine solution properties as afunction of concentration. In addition, reconstituted vials were storedat two temperatures for two time points to investigate the stability ofthe reconstituted solutions. Samples were inspected visually andanalyzed for pH, osmolality, color, and potency after reconstitution.Instrumental particle testing was performed immediately followingreconstitution, as well as after storage at for 8 and 24 hours at 5 and25° C., to look for evidence of precipitation. Testing was repeatedafter the lyophilized vials had been stored at 5° C. for approximatelysix months.

Lyophilized vial samples were reconstituted with diluent aliquots of 10,15, and 20 mg/mL, and tested for potency, pH, osmolality, color, andvisual inspection. Reconstituted vials were also tested for instrumentalparticle counts immediately after reconstitution, and after subsequentstorage at 5 and 25° C., for 8 and 24 hours. Reconstitution wasperformed using filtered distilled water.

An additional test interval was conducted after the lyophilized vialshad been stored for approximately 6 months at 5° C. Vials werereconstituted to 15 mg/mL with filtered distilled water and were testedfor potency, pH, osmolality, color, and visual appearance. Vials werealso examined for instrumental particle counts.

Results of potency, pH, visual inspection, osmolality, and color testingare given in Tables 7-10. TABLE 7 Results for Samples Reconstituted with15 mL Diluent (Initial Interval) Potency Color Osmolality Sample (mg/mL)PH Visual (ks) (mOsmol/kg) 15-A 15.4 4.01 pass 10.0 960 15-B 17.6 4.05pass 7.0 967 15-C 15.0 4.07 pass 10.0 976

TABLE 8 Results for Samples Reconstituted with 20 mL Diluent (InitialInterval) Potency Color Osmolality Sample (mg/mL) PH Visual (ks)(mOsmol/kg) 20-A 11.5 3.98 pass 6.5 693 20-B 11.7 3.98 pass 7.0 696 20-C11.4 3.97 pass 9.5 693

TABLE 9 Results for Samples Reconstituted with 30 mL Diluent (InitialInterval) Potency Color Osmolality Sample (mg/mL) pH Visual (ks)(mOsmol/kg) 30-A 8.1 3.99 pass 4.0 447 30-B 8.0 4.00 pass 3.5 447 30-C8.5 3.98 pass 5.0 447

TABLE 10 Results for Samples Reconstituted with 20 mL Diluent (6 MonthInterval) Potency Color Osmolality Sample (mg/mL) pH Visual (ks)(mOsmol/kg) 20-A(6 MO) 12.26 4.15 pass 17 687 20-B(6 MO) 12.32 4.16 pass15 688 20-C(6 MO) 12.20 4.16 pass 17 687

Zileuton concentration in the reconstituted samples were consistent withthe dilution factors, when accounting for the volume occupied by thelyophilizate (drug and CAPTISOL Cyclodextrin). The pH data for thereconstituted vials indicated that all solutions have a pH of 4.0±0.1,after reconstitution. Osmolality data shows an increase in osmolalitywith increasing formulation concentration (decreasing diluent volume).

Potency values for samples reconstituted after six months storage wereconsistent with stable product. The pH data at the six month intervalindicated an insignificant change in pH. Osmolality data was consistentwith the data from the initial interval.

All vials passed visual inspection. The instrumental particle counts permL for all of the samples tested were within the current USP particlelimits for 20 mL Small Volume Injection (SVI) solutions.

While the present invention has been described with references tocertain preferred embodiments, these preferred embodiments are in no waymeant to limit the scope of the present invention in any way. The scopeof the present invention is defined by the claims which follow and allequivalents to which they are entitled under law.

1. A pharmaceutical composition comprising an inclusion complex of alipoxygenase inhibitor and a cyclodextrin, wherein the lipoxygenaseinhibitor is present in the composition at a therapeutically effectiveconcentration.
 2. The pharmaceutical composition of claim 1 furtherincluding a pharmaceutically acceptable excipient.
 3. The pharmaceuticalcomposition of claim 1 wherein the lipoxygenase inhibitor is selectedfrom the group consisting of a 5-lipoxygenase inhibitor, a12-lipoxygenase inhibitor and an inhibitor of 5- and 12-lipoxygenase. 4.The pharmaceutical composition of claim 3 wherein the cyclodextrin isselected from the group consisting of α-cyclodextrin, β-cyclodextrin,γ-cyclodextrin and derivatives thereof.
 5. The pharmaceuticalcomposition of claim 4 wherein the lipoxygenase inhibitor is a5-lipoxygenase inhibitor.
 6. The pharmaceutical composition of claim 5wherein the cyclodextrin is a β-cyclodextrin or a derivative thereof. 7.The pharmaeutical composition of claim 3 wherein the lipoxygenaseinhibitor has the Formula (II):

wherein R₅ is C₁ or C₂ alkyl or NR₆R₇, where R₆ and R₇ are independentlyselected from hydrogen and C₁ or C₂ alkyl; B is CH₂ or CHCH₃ ; and W isoxygen or sulfur.
 8. The pharmaceutical composition of claim 7 whereinthe cyclodextrin is selected from the group consisting of a2-hydroxypropyl-β-cyclodextrin and a sulfobutyl derivatizedβ-cyclodextrin.
 9. The pharmaceutical composition of claim 8 wherein thelipoxygenase inhibitor has the Formula (III):


10. The pharmacuetical composition of claim 9 wherein the β-cyclodextrinis sulfobutylether(7)-β-cyclodextrin.
 11. The pharmaceutical compositionof claim 10 wherein the concentration of the lipoxygenase inhibitor isfrom about 0.1 mg/mL to about 200 mg/mL.
 12. The pharmaceuticalcomposition of claim 12 wherein the concentration of the lipoxygenaseinhibitor is from about 5 mg/mL to about 50 mg/mL.
 13. Thepharmaceutical composition of claim 12 wherein the molar ratio of thelipoxygenase inhibitor to the cyclodextrin is from about 10:1 to about1:
 10. 14. The pharmaceutical composition of claim 13 wherein the5-lipoxygenase inhibitor is present at a concentration of from about 0.1mg/mL to about 200 mg/mL and the cyclodextrin is present at aconcentration of from about 10 mg/mL to about 500 mg/mL.
 15. Thepharmaceutical composition of claim 14 further comprising a buffer. 16.The pharmaceutical composition of claim 15 wherein the buffer is acitrate buffer.
 17. The pharmaceutical composition of claim 16 whereinthe concentration of the citrate buffer is from about 5 mM to about 500mM.
 18. The pharmaceutical composition of claim 17 having a pH of fromabout 3 to about
 9. 19. The pharmaceutical composition of claim 18formulated for parenteral administration.
 20. A parenteral formulationcomprising an inclusion complex of a lipoxygenase inhibitor and acyclodextrin wherein the lipoxygenase inhibitor is present at atherapeutically effective concentration.
 21. The parenteral formulationof claim 20 wherein the lipoxygenase inhibitor is a 5-lipoxygenaseinhibitor and the cyclodextrin is a 13-cyclodextrin or derivativethereof.
 22. The parenteral formulation of claim 21 wherein the molarratio of the 5-lipoxygenase inhibitor to the 13-cyclodextrin is fromabout 10:1 to about 1:
 10. 23. The parenteral formulation of claim 22wherein the concentration of the 5-lipoxygenase inhibitor is from about0.1 mg/mL to about 200 mg/mL and the concentration of 13-cyclodextrin isfrom about 4 mM to about 900 mM.
 24. The parenteral formulation of claim23 wherein the concentration of the 5-lipoxygenase inhibitor is fromabout 5 mg/mL to about 50 mg/mL and the 13-cyclodextrin is present at aconcentration of from about 20 mM to about 500 mM.
 25. The parenteralformulation of claim 24 further comprising a buffer.
 26. The parenteralformulation of claim 25 wherein the buffer is a citrate buffer presentat a concentration of from about 5 mM to about 500 mM.
 27. Theparenteral formulation of claim 26 wherein the 5-lipoxygenase inhibitoris present at a concentration of from about 0.1 mg/mL to about 200mg/mL, the β-cyclodextrin is present at a concentration of from about 10mM to about 500 mM, the citrate buffer is present at a concentration offrom about 5mM to about 15mM and wherein the parenteral formulation hasa pH of from about 3 to about
 9. 28. The parenteral formulation of claim27 wherein the β-cyclodextrin is selected from the group consisting of a2-hydroxypropyl-β-cyclodextrin and a sulfobutyl derivatizedβ-cyclodextrin and the 5-lipoxygenase inhibitor has the formula (III):


29. A dried formulation comprising an inclusion complex of alipoxygenase inhibitor and a cyclodextrin wherein the inclusion complexhas a solubility of at least 0.2 mg/mL and the lipoxygenase inhibitor ispresent at a therapeutically effective concentration.
 30. The driedformulation of claim 29 wherein the lipoxygenase inhibitor is a5-lipoxygenase inhibitor and the cyclodextrin is a β-cyclodextrin. 31.The dried formulation of claim 30 wherein the β-cyclodextrin is selectedfrom the group consisting of 2-hydroxypropyl-β-cyclodextrins andsulfobutyl derivatized β-cyclodextrins and the 5-lipoxygenase inhibitorhas the formula


32. The dried formulation of claim 31 further comprising a buffer. 33.The dried formulation of claim 32 wherein upon dissolution with anaqueous diluent the concentration of the 5-lipoxygenase inhibitor isfrom about 0.1 mg/mL to about 200 mg/mL.
 34. The dried formulation ofclaim 33 adapted for oral, rectal, nasal, pulmonary, ophthalmic,vaginal, aural, topical, buccal, transdermal, intravenous,intramuscular, subcutaneous, intradermal, intraocular, intracerebral,intralymphatic, intraarticular, intrathecal or intraperitonealadministration.
 35. The dried formulation of claim 29 wherein saidformulation is prepared by a method selected from the group consistingof lyophilization, spray-drying and super-critical fluid extraction, 36.A composition comprising an inclusion complex of a lipoxygenaseinhibitor and a cyclodextrin.
 37. The composition of claim 36 whereinthe lipoxygenase inhibitor has the Formula (II):


38. The composition of claim 37 wherein the cyclodextrin is selectedfrom the group consisting of α-cyclodextrin, β-cyclodextrin,γ-cyclodextrin and derivatives thereof.
 39. The composition of claim 38wherein the cyclodextrin is a β-cyclodextrin or a derivative thereof.40. The composition of claim 38 wherein the cyclodextrin is selectedfrom the group consisting of a 2-hydroxypropyl-β-cyclodextrin and asulfobutyl derivatized β-cyclodextrin.
 41. A method of making an aqueoussolution of an inclusion complex of a lipoxygenase inhibitor and aβ-cyclodextrin comprising the steps of: a. preparing an aqueous buffersolution; b. dissolving a β-cyclodextrin in the buffer solution; and c.adding a lipoxygenase inhibitor to the β-cyclodextrin and buffersolution to create a mixture thereof.
 42. The method of making theaqueous solution of claim 41 further comprising the step of stirringand/or sonicating the mixture of lipoxygenase inhibitor and theβ-cyclodextrin.
 43. The method of making the aqueous solution of claim41 further comprising the step of adjusting the pH of the buffersolution to be from about 3 to about
 9. 44. The method of making anaqueous solution of claim 42 wherein the solution has a concentration of0.1 mg/mL to about 200 mg/mL of the 5-lipoxygenase inhibitor, aconcentration of from about 10 mM to about 500 mM of the β-cyclodextrin,and wherein the buffer is a citrate buffer present at a concentration offrom about 5 mM to about 15 mM.
 45. The method of making an aqueoussolution of claim 43 wherein the β-cyclodextrin is selected from thegroup consisting of a 2-hydroxypropyl-β-cyclodextrin and a sulfobutylderivatized β-cyclodextrin and the 5-lipoxygenase inhibitor has theformula (III):


46. A method of treating a condition mediated by lipoxygenase activityin a mammal in need thereof comprising the steps of administering aformulation comprising an inclusion complex of a lipoxygenase inhibitorand cyclodextrin, wherein said formulation includes a therapeuticallyeffective concentration of the lipoxygenase inhibitor.
 47. The method ofclaim 46 wherein the condition is selected from the group consisting ofasthma, rheumatoid arthritis, gout, psoriases, allergic rhinitis,respiratory distress syndrome, chronic obstructive pulmonary disease,acne, atopic dermatitis, atherosclerosis, aortic aneurysm, sickle celldisease, acute lung injury, ischemia/reperfusion injury, nasalpolyposis, inflammatory bowel disease, irritable bowel syndrome, cancer,tumors, respiratory syncytial virus, sepsis, endotoxin shock andmyocardial infarction.
 48. The method of claim 46, wherein the conditionis an inflammatory condition.
 49. The method of claim 46 wherein thelipoxygenase inhibitor is selected from the group consisting of a5-lipoxygenase inhibitor, a 12-lipoxygenase inhibitor and an inhibitorof 5- and 12-lipoxygenase and the cyclodextrin is selected from thegroup consisting of α-cyclodextrin, β-cyclodextrin and 7-cyclodextrin ora derivative thereof.
 50. The method of claim 46 wherein the formulationis an aqueous solution and the lipoxygenase inhibitor is present at aconcentration of about 0.1 mg/mL to about 200 mg/mL.
 51. The method ofclaim 46 wherein the cyclodextrin is selected from the group consistingof a 2-hydroxypropyl-β-cyclodextrin and a sulfobutyl derivatizedβ-cyclodextrin and the lipoxygenase inhibitor has the formula (III):


52. The method of claim 51 wherein the formulation is administeredparenterally.
 53. The method of claim 52 wherein the formulation is alyophilizate.
 54. The method of claim 53 wherein the formulation isadministered orally.